Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer

Abstract

Summary Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a dismal 5-year survival rate of 8% 1 . Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in >90% of PDAC, and its signaling surrogates has yielded encouraging preclinical results with experimental agents 2 - 4 . However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies 5 , 6 . Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signaling essential for malignant transformation and tumor maintenance. Insights into the complexity of the functional surfaceome have been technologically limited until recently, and, in the case of PDAC, the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signaling remains largely unexplored. Here, we developed an unbiased, functional target discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which uncovered syndecan-1 (SDC1) as a protein upregulated at the cell surface by KRAS*. Cell surface localization of SDC1 is essential for disease maintenance and progression, where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth. Thus, our study forges a mechanistic link between KRAS* signaling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.

Dynamic CD138 surface expression regulates switch between myeloma growth and dissemination

“…Many factors can be involved in the regulation of the CD138 surface expression, although not in the context of myeloma dissemination. Syntenin and PIP2 have been implicated in controlling endocytic trafficking of CD138 via Arf6-labeled endosomes in epithelial cells [11]. Recycling to the surface was blocked by serum starvation, whereas internalization was not dependent on these adaptors.…”

“…Syndecan-1 is a large glycoprotein, carrying heparan sulfate moieties, expressed widely on BM hematopoietic cells, endothelial cells, and on some breast cancer cells. Among its many functions, CD138 has been implicated in wound healing [8], cell adhesion [9], endocytosis [10], and macropinocytosis [11], and may translocate to the nucleus [12]. Hundreds of proteins can bind to CD138, including extracellular matrix components and integrins for adhesion [13].…”

ATM inhibition drives metabolic adaptation via induction of macropinocytosis

“…Previous studies have shown that macropinocytosis is one mechanism whereby cancer cells scavenge nutrients from the microenvironment to support survival and proliferation (Commisso et al, 2013;Davidson et al, 2017;Hodakoski et al, 2019;Kamphorst et al, 2015;Kim et al, 2018;Lee et al, 2019;Palm, 2019;Palm et al, 2017;Recouvreux and Commisso, 2017;Redelman-Sidi et al, 2018;Yao et al, 2019;Zhang and Commisso, 2019). Due to its large size, fluorescently-labeled dextran is used as a surrogate for macropinocytosis as it cannot be taken up through other endocytic pathways Ivanov, 2008).…”

“…Macropinocytosis is an endocytic process whereby cells take up fluid, macromolecules, metabolites, and other cargo from the surrounding microenvironment (King and Kay, 2019;Palm, 2019;Zhang and Commisso, 2019). Many studies have evaluated the critical role of macropinocytosis as a nutrient scavenging mechanism in cancers under nutrientdeprived conditions (Commisso et al, 2013;Davidson et al, 2017;Hodakoski et al, 2019;Kamphorst et al, 2015;Kim et al, 2018;Redelman-Sidi et al, 2018;Tejeda-Munoz et al;Yao et al, 2019). To date, these studies have focused on cancers with high PI3K activity, such as those with mutant RAS or PTEN loss, which act upstream of the Rac1-Pak1 actin remodeling pathway to promote macropinosome formation .…”

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

“…Inhibition of KRAS-enhanced macropinocytosis represents another possibility to target mutant cancer cells by interfering with their ability to internalize extracellular fluids-containing nutrients. Although the molecular basis of KRAS-driven macropinocytosis is not yet clearly demonstrated, KRAS-dependent expression of Syndecan 1 at the cell surface was recently identified as a molecular mechanism regulating macropinocytosis and indicated as a putative therapeutic target [23]. Moreover, the high internalization of albumin through macropinocytosis can be explored as a drug delivery strategy.…”