Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling 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 signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (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* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface-where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth-is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.
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KrasG12D inactivation upon doxycycline withdrawal led to rapid and continuous downregulation of surface SDC1 levels during the first week.
“As we previously reported, KrasG12D inactivation upon doxycycline withdrawal led to rapid and continuous downregulation of surface SDC1 levels during the first week.12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
The paper reports that KRAS extinction caused a rapid decrease in membrane SDC1, and Extended Data Figure 3 describes SDC1 staining after 48 hours without doxycycline. The passages do not establish that surface SDC1 continued to decline throughout the first week. (LLM, conf=0.86)
Experimental — accuracy not yet measured70%-90% of PDAC cases exhibit high SDC1 expression.
“While 70%–90% of PDAC cases exhibit high SDC1 expression,12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
The paper reports detecting SDC1 in human PDAC lesions and cites datasets showing increased expression in PDAC tissue versus normal pancreas (main text, page unavailable). It does not report that 70%–90% of PDAC cases have high SDC1 expression. The Extended Data figure describes 13 of 20 cell lines as having high membrane expression, but cell lines are not PDAC cases. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn the iKras GEM model, acute extinction of mutant KRAS results in downregulation of SDC1 expression, coinciding with suppression of MAPK signaling.
“In the iKras GEM model, acute extinction of mutant KRAS results in downregulation of SDC1 expression, coinciding with suppression of MAPK signaling, as evidenced by reduced ERK phosphorylation.12,17”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
The main-text passage labeled Abstract (page unavailable) reports that acute KRAS extinction in the iKras model rapidly reduced SDC1 at the cell surface, but explicitly says SDC1 mRNA and total protein expression were unaffected. It also links SDC1 membrane localization to the MAPK pathway. The Extended Data captions describe phospho-ERK blots under KRAS ON/OFF conditions, but the text does not explicitly report reduced ERK phosphorylation. (LLM, conf=0.90)
Experimental — accuracy not yet measuredARF6 activity downstream of oncogenic KRAS signaling controls SDC1 surface localization in PDAC cells.
“Our previous study indicates that ARF6 activity downstream of oncogenic KRAS signaling controls SDC1 surface localization in PDAC cells.12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
KRAS*-driven SDC1 membrane expression plays a critical role in PDAC progression.
“Recently, we identified syndecan-1 (SDC1), a cell surface proteoglycan, as a key effector downstream of KRAS∗ and demonstrated that KRAS∗-driven SDC1 membrane expression plays a critical role in PDAC progression.”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
ARF6 is a small GTPase that drives KRAS*-mediated SDC1 membrane recycling in KRAS*-dependent PDAC cells.
“ARF6 is a small GTPase that drives KRAS∗-mediated SDC1 membrane recycling in KRAS∗-dependent PDAC cells.12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
Reduction of surface SDC1 expression following KRAS* inactivation was regulated through ARF6-mediated SDC1 trafficking, independent of SDC1 transcription or protein expression.
“We previously demonstrated that the reduction of surface SDC1 expression following KRAS∗ inactivation was regulated through ARF6-mediated SDC1 trafficking,12 independent of SDC1 transcription or protein expression.12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
Surface localization of SDC1, driven by KRAS* activation, plays a crucial role in maintaining macropinocytosis in PDAC.
“Our previous study demonstrated that the surface localization of SDC1, driven by KRAS∗ activation, plays a crucial role in maintaining macropinocytosis in PDAC.12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
RAC1 activity is mediated by SDC1 to promote macropinocytosis.
“Our previous study showed that RAC1 activity is mediated by SDC1 to promote macropinocytosis.12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
Surface localization of SDC1 is regulated through the MAPK-PSD4-ARF6 axis, wherein MAPK activation induces PSD4 expression, leading to ARF6 activation and subsequent SDC1 trafficking to the membrane.
“Previously, we demonstrated that surface localization of SDC1 is regulated through the MAPK-PSD4-ARF6 axis, wherein MAPK activation induces PSD4 expression, leading to ARF6 activation and subsequent SDC1 trafficking to the membrane.12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
SDC1 plays a critical role for oncogenic KRAS-mediated macropinocytosis.
“Previously, we demonstrated that SDC1 plays a critical role for oncogenic KRAS-mediated macropinocytosis,12”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [12]
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References 31 · Cited by 214
Research works printed but not linked: 5
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- Authors
- Yao, W., Rose, J. L., Wang, W., Seth, S., Jiang, H., Taguchi, A., Liu, J., Yan, L., Kapoor, A., Hou, P., Chen, Z., Wang, Q., Nezi, L., Xu, Z., Yao, J., Hu, B., Pettazzoni, P. F., Ho, I. L., Feng, N., Ramamoorthy, V., Jiang, S., Deng, P., Ma, G. J., Den, P., Tan, Z., Zhang, S. X., Wang, H., Wang, Y. A., Deem, A. K., Fleming, J. B., Carugo, A., Heffernan, T. P., Maitra, A., Viale, A., Ying, H., Hanash, S., DePinho, R. A., & Draetta, G. F.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Draetta, Giulio F.
- ORCID
- Yao, Wantong
- Rose, Johnathon L.
- Wang, Wei
- Seth, Sahil
- Jiang, Hong
- Taguchi, Ayumu
- Liu, Jintan
- Hou, Pingping
- Wang, Qiuyun
- Nezi, Luigi
- Xu, Zhaohui
- Yao, Jun
- Hu, Baoli
- Pettazzoni, Piergiorgio F.
- Ho, I Lin
- Feng, Ningping
- Jiang, Shan
- Deng, Pingna
- Tan, Zhi
- Wang, Huamin
- Wang, Y. Alan
- Deem, Angela K.
- Fleming, Jason B.
- Carugo, Alessandro
- Heffernan, Timothy P.
- Maitra, Anirban
- Viale, Andrea
- Ying, Haoqiang
- Hanash, Samir
- DePinho, Ronald A.
- Draetta, Giulio F.
- Venue
- Nature
- Published
- 2019-03-27
- Volume
- 568
- Issue
- 7752
- Pages
- 410-414
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6661074
- OpenAlex
- W2925187261
- Cited by
- 214
- References
- 31
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 29 · 2023: 21 · 2022: 46 · 2021: 37 · 2020: 20 · 2019: 10
- FWCI
- 11.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (P30CA016672, P01CA117969)
- National Institute of Biomedical Imaging and Bioengineering (R21EB016212)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- syndecan-1, macropinocytosis, pancreatic ductal adenocarcinoma, cancer metabolism, therapeutic target discovery, surface protein expression
- MeSH terms
- ADP-Ribosylation Factor 6, Animals, Female, Humans, Male, Pancreatic Neoplasms, Pinocytosis, Signal Transduction, Proto-Oncogene Proteins p21(ras), Disease Progression, Guanine Nucleotide Exchange Factors, ADP-Ribosylation Factors, Carcinoma, Pancreatic Ductal, Cell Proliferation, Mice, Syndecan-1
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