Autocrine laminin-5 ligates {alpha}6{beta}4 integrin and activates RAC and NF{kappa}B to mediate anchorange-independent survival of mammary tumors

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express α6β4 integrin. Here, we show that autocrine LM-5 mediates anchorage independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail–truncated α6β4 integrin. α6β4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of β4 integrin is necessary for basal and epidermal growth factor–induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional β1 and β4 integrin through activation of NFκB, and overexpression of NFκB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5–α6β4 integrin–RAC–NFκB signaling

Autocrine laminin-5 ligates α6β4 integrin and activates RAC and NFκB to mediate anchorage-independent survival of mammary tumors

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express α6β4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail–truncated α6β4 integrin. α6β4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of β4 integrin is necessary for basal and epidermal growth factor–induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional β1 and β4 integrin through activation of NFκB, and overexpression of NFκB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5–α6β4 integrin–RAC–NFκB signaling

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Spatial-mechanical regulation of mammary morphogenesis and therapeutic resistance

Apoptosis resistance plays an important role in breast cancer progression and metastasis and is critical for the pathogenesis of therapeutic resistance. Research aimed at understanding the molecular basis for chemotherapy and radiation resistance has traditionally viewed breast cancer as a cell autonomous disease. Yet, epigenetic phenomena such as cell shape and the organizational features of a tissue, as induced by the extracellular matrix, are known to affect gene expression to regulate the malignant phenotype and to promote tumor behavior. The chemical composition and the three-dimensional spatial organization of the matrix dictate its mechanical properties and apoptosis responsiveness of mammary epithelial cells to exogenous death cues (Weaver et al., Cancer Cell 2002). Moreover, breast cancers often display heterogeneity in tissue stiffness and response to therapy at the primary site, and breast cancers metastasize to multiple tissues that each has distinct mechanical properties. Therefore, an investigation was conducted to determine whether matrix stiffness could modulate apoptosis resistance of mammary epithelial cells (MECs). In a compliant three-dimensional matrix, we showed that mammary tumors have enhanced autocrine laminin-5 and α6β4 integrin expression, which stimulate Rac and NFκB activity to drive apoptosis resistance. Moreover, we showed that mammary tumorigenesis is coincident with an increase in tissue stiffness that is associated with enhanced collagen deposition. We then determined that tumor-associated mammary tissue stiffness could promote β1 integrin-associated focal adhesions to alter cell signaling through ERK and Rho to enhance cell growth and disrupt MEC morphogenesis. We finally demonstrated that matrix stiffness could promote JNK activity and apoptosis induction in response to chemotherapeutics and radiation. We could show that inhibiting JNK increases survival of MECs on a stiff matrix treated with various chemotherapies and that activating JNK enhances apoptosis of MECs on a soft matrix. Collectively, these data illustrate the underlying mechanisms by which ECM stiffening during tumor progression could promote the malignant phenotype, and how the mechanical properties of pathological breast tissue or different sites of metastasis could affect therapeutic efficacy.

Spatial-mechanical regulation of mammary morphogenesis and therapeutic resistance

Apoptosis resistance plays an important role in breast cancer progression and metastasis and is critical for the pathogenesis of therapeutic resistance. Research aimed at understanding the molecular basis for chemotherapy and radiation resistance has traditionally viewed breast cancer as a cell autonomous disease. Yet, epigenetic phenomena such as cell shape and the organizational features of a tissue, as induced by the extracellular matrix, are known to affect gene expression to regulate the malignant phenotype and to promote tumor behavior. The chemical composition and the three-dimensional spatial organization of the matrix dictate its mechanical properties and apoptosis responsiveness of mammary epithelial cells to exogenous death cues (Weaver et al., Cancer Cell 2002). Moreover, breast cancers often display heterogeneity in tissue stiffness and response to therapy at the primary site, and breast cancers metastasize to multiple tissues that each has distinct mechanical properties. Therefore, an investigation was conducted to determine whether matrix stiffness could modulate apoptosis resistance of mammary epithelial cells (MECs). In a compliant three-dimensional matrix, we showed that mammary tumors have enhanced autocrine laminin-5 and α6β4 integrin expression, which stimulate Rac and NFκB activity to drive apoptosis resistance. Moreover, we showed that mammary tumorigenesis is coincident with an increase in tissue stiffness that is associated with enhanced collagen deposition. We then determined that tumor-associated mammary tissue stiffness could promote β1 integrin-associated focal adhesions to alter cell signaling through ERK and Rho to enhance cell growth and disrupt MEC morphogenesis. We finally demonstrated that matrix stiffness could promote JNK activity and apoptosis induction in response to chemotherapeutics and radiation. We could show that inhibiting JNK increases survival of MECs on a stiff matrix treated with various chemotherapies and that activating JNK enhances apoptosis of MECs on a soft matrix. Collectively, these data illustrate the underlying mechanisms by which ECM stiffening during tumor progression could promote the malignant phenotype, and how the mechanical properties of pathological breast tissue or different sites of metastasis could affect therapeutic efficacy.

Developing and validating model systems for immuno-oncology.

Owing to clinical success of immune-checkpoint blockade, immunotherapy is becoming a cornerstone of modern oncology, and immuno-oncology is at the forefront of basic cancer research. This commentary outlines future opportunities for immuno-oncology modeling

Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling

Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling