Hotspot mutant p53-R273H enhances mitochondrial biogenesis and cell migration in primary colorectal cancer in response to oxaliplatin

Abstract

Oxaliplatin is commonly known as a successful chemotherapy for advanced colorectal cancer, improving patient survival and eradicating micro-metastases, but its use in early stages remains controversial. Mitochondria fuel energy-intensive programs such as cell migration, yet how oxaliplatin regulates the mitochondrial network in CRC - and how TP53 context shapes this - remains unclear. We investigated a matched pair of CRC cell lines from the same patient - SW480 (primary) and SW620 (lymph-node metastasis) - both harboring TP53-R273H mutation, to define differential responses in mitochondrial biogenesis, dynamics and respiration and the mechanisms underlying them. The results indicate that primary-derived colorectal cancer cell line increased cell migration, mitochondrial biogenesis, and mitochondrial respiration capacity in response to oxaliplatin through a new and firstly described gain-of-function (GOF) of p53-R273H. Additionally, in the primary-derived CRC line, oxaliplatin elicited fate heterogeneity - coexisting apoptotic and senescent fractions alongside an R273H-driven, bioenergetically primed migratory subpopulation - together with increased mitochondrial biogenesis and respiratory capacity; by contrast, the metastatic-derived line was more sensitive and displayed structural mitochondrial injury with reduced maximal respiration. More broadly, this work underscores the importance of p53 gain-of-function mutations in CRC: the same GOF (TP53-R273H) amplifies cell migration by coupling an enhanced mitochondrial biogenesis/OXPHOS program to motility. Oxaliplatin further accentuates this energetically primed, pre-metastatic state, arguing for mitochondrial-targeted combination strategies in early-stage CRC