3 research outputs found
Autophagy in Epidermis.
PhDOrganâtransplant recipients (OTRs) on a new class of immunosuppressants,
rapamycin and its analogues, have reduced cutaneous Squamous Cell Carcinomas
(cSCCs). Rapamycin, an mTORC1 inhibitor, is also a known autophagy inducer in
experimental models. Autophagy, which literally means selfâeating, is a cell survival
mechanism but can also lead to cell death. Therefore, the main hypothesis behind
this work is that rapamycin prevents epidermal tumourigenesis by either affecting
epidermal mTOR regulation of autophagy and/or selectively affecting epidermal
AKT isoform activity.
Epidermal keratinocytes move from the proliferating basal layer upwards to the
granular layers where they terminally differentiate, forming a layer of flattened,
anucleate cells or squames of the cornified layer which provides an essential
environmental barrier. However, epidermal terminal differentiation, a specialised
form of cell death involving organelle degradation, is poorly understood.
The work presented in this thesis shows that analysis of the autophagy marker
expression profile during foetal epidermal development, indicates autophagy is
constitutively active in the terminally differentiating granular layer of epidermis.
Therefore, I hypothesize that autophagy is a mechanism of organelle degradation
during terminal differentiation of granular layer keratinocytes.
In monolayer keratinocytes, activation of terminal differentiation is accompanied by
autophagic degradation of nuclear material, nucleophagy. This suggests that
constitutive autophagy is a proâdeath mechanism required for terminal
differentiation. In cultured keratinocytes and in epidermal cultures, rapamycinmediated
mTORC1 inhibition strongly increases AKT1 activity as well as upâregulates
constitutive granular layer autophagy promoting terminal differentiation.
Therefore, autophagy is an important fundamental process in keratinocytes which
may be the mechanism by which terminally differentiating keratinocytes of the epidermal granular layer degrade their organelles required for barrier formation.
This may have implications for the treatment of patients with barrier defects like
psoriasis. In immunosuppressed OTRs, rapamycin may promote epidermal
autophagy and AKT1 activity adding to its antiâtumourigenic properties
T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments
It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. Here we studied a mouse model of human T-cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single-cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting that a stochastic mechanism underlies these processes. Yet, although T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells while perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment, rather than specific bone marrow stroma, to combat the invasion by and survival of chemo-resistant T-ALL cells