Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, , a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα CAFs. Whereas -competent CAFs stimulate the growth of tumor cells in an orthotopic model,-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of in pancreatic tumor cells makes them insensitive to the inhibitory effect of-null CAFs. As a consequence, germline ablation of does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed,, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

“…In contrast, the myofibroblast markers Acta2 and Tagln were expressed by a portion of FB3. These data support the presence of previously described, mutually exclusive, inflammatory (FB1) and myofibroblastic (FB3) CAF subtypes [22–24]. Interestingly, FB3 also expressed numerous MHC-II–associated genes (Fig.…”

“…The IL6+ fibroblasts were also positive for PDGFRα and numerous other cytokines and therefore termed inflammatory CAFs or “iCAFs.” The immunohistochemistry of human and mouse PDA tissue showed distal IL6+ stroma as a distinct population from the peritumoral αSMA+ stroma. Subsequent studies in PDA GEMMs demonstrated that the iCAF population can mediate pro-tumorigenic properties and is a potential therapeutic target in an attempt to sensitize PDA to immunotherapeutic strategies [23, 24].…”

Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression

“…A major question in the field is what role do CAFs play in PDAC tumorigenesis? Several studies have demonstrated that CAFs are tumor promoting (Djurec et al, 2018;Hwang et al, 2008), while others have suggested tumor restrictive roles (Özdemir BC, 2014;Rhim et al, 2014). One possible explanation for the seemingly paradoxical findings is that not all CAFs are created equally, as it is now appreciated that there is great heterogeneity in the fibroblastic population within the tumor microenvironment (Ohlund et al, 2014).…”

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

“…In addition, FAP-α-positive CAFs were identified as major source of CXCL12, and blockade via AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, or genetic ablation of FAP-α-positive CAFs induced rapid T-cell accumulation and subsequent sensitisation to T-cell checkpoint antagonists 89. Recently, Guerra and colleagues identified murine Saa3 , a member of the serum amyloid A (SAA) apolipoprotein family, as important pro-tumourigenic factor of PDGFR-α-positive CAFs 81. The human orthologue SAA1 was overexpressed in CAFs of patients with PDA and correlated with worse prognosis indicating a potential novel therapeutic target 81.…”

“…Recently, Guerra and colleagues identified murine Saa3 , a member of the serum amyloid A (SAA) apolipoprotein family, as important pro-tumourigenic factor of PDGFR-α-positive CAFs 81. The human orthologue SAA1 was overexpressed in CAFs of patients with PDA and correlated with worse prognosis indicating a potential novel therapeutic target 81. Another interesting study from Bousquet and colleagues in Toulouse recently showed that selective pharmacological activation of somatostatin receptors in CAFs blocks the mTOR/4E-BP1 pathway and subsequent synthesis of several CAF-derived secreted proteins,82 including IL-6 that resulted in sensitisation to gemcitabine and inhibition of cancer cell metastasis 90…”