CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

Abstract

Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

“…In line with this study, the existence of a p53-driven hierarchy in PDAC was recently reported, where GoF p53mut cancer cells educate CAFs partially via tumour necrosis factor-alpha (TNF-a) and nuclear factor-kB (NFkB) signalling to create a permissive environment with pro-invasive cues via deposition of perlecan, an ECM proteoglycan [47]. Strikingly, these p53mut-educated CAFs caused invasion of normally poorly invasive p53null tumour cells (to the same extent as the highly invasive p53mut cancer cells) through both direct and long-range paracrine signalling [47]. Furthermore, p53null-educated CAFs, which create an environment less permissive to invasion and metastasis than p53mut-educated CAFs, can be subsequently re-educated by either p53mut cancer cells or their matched CAFs to, in turn, behave like p53mut-educated CAFs [47].…”

“…Instead, there are several conventional and emerging biomarkers that can be used in concert to identify this diverse stromal population. The most commonly used PDAC CAF biomarkers are alpha-smooth muscle actin (a-SMA), fibroblast activation protein (FAP), vimentin, fibroblast-specific protein 1 (FSP1), podoplanin (PDPN/gp38), and platelet-derived growth factor receptor alpha and/or beta (PDGFRa/b) [23,47]; however, this list is neither all-inclusive nor entirely CAF specific [46]. In the pancreas specifically, PSC-derived CAFs lose lipid droplet expression once activated [30].…”

A framework for advancing our understanding of cancer-associated fibroblasts

“…Work in PDAC has shown how KRAS mutation or different p53 mutational status can influence CAFs 111,136 . Mutant p53 drives TNF production by cancer cells, leading to enhanced matrix remodelling and perlecan expression by CAFs 136 . However, such studies do not preclude additional nongenetic factors influencing CAF subtype.…”

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

“…The functional relevance of squamous trans-differentiation in pancreatic cancer was unclear until recently, when studies from several laboratories, including our own, demonstrated that the transcription factor TP63 (delta N isoform, hereafter referred to as TP63 for simplicity) is the master regulator of the adenosquamous phenotype in PDA (Andricovich et al, 2018;Hamdan and termed iCAFs, have low expression of myCAF markers and instead produce high levels of inflammatory cytokines, such as IL-6, CXCL1, and LIF (Öhlund et al, 2017). Although the iCAF/myCAF ratio, the extent of neutrophil infiltration, and the overall level of stromal inflammation can vary significantly between PDA patients, the underlying features of cancer cells that drive these differences are only beginning to be understood (Vennin et al, 2019).…”