Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

Background & Aims Gastric cancer evolves in the setting of a pathologic mucosal milieu characterized by both loss of acid-secreting parietal cells and mucous cell metaplasias. Indeed, mucous cell metaplasia is considered the critical preneoplastic lesion for gastric cancer. Previous investigations have shown that infection of mice with Helicobacter felis or induction of acute parietal cell loss with the drug DMP-777 leads to the emergence of a type of metaplasia designated spasmolytic polypeptide-expressing metaplasia (SPEM). We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells. Methods Taking advantage of the chief cell-restricted expression of Mist1-Cre-ER^T2, we used lineage mapping to examine whether SPEM lineages were derived from chief cells in 3 independent models of induction by DMP-777 treatment, L-635 treatment, or H felis infection. Results Treatment of mice with L-635 for 3 days led to rapid parietal cell loss, induction of a prominent inflammatory infiltrate, and emergence of SPEM. In all 3 models, SPEM developed, at least in part, from transdifferentiation of chief cells. We further found that acute parietal cell loss in the setting of inflammation (L-635 treatment) led to more rapid induction and expansion of SPEM derived from transdifferentiation of chief cells. Conclusions These studies provide direct evidence by lineage tracing that SPEM evolves from differentiated chief cells. Thus, mature gastric chief cells have the ability to act as cryptic progenitors and reacquire proliferative capacity within the context of mucosal injury and inflammation.

Gastric adenocarcinoma of the intestinal type is believed to develop through a series of histopathologic stages, originally described by Correa,¹ Correa P. A human model of gastric carcinogenesis. Cancer Res. 1988; 48 : 3554-3560 PubMed Google Scholar that include chronic gastritis, gastric atrophy, intestinal metaplasia, dysplasia, and finally cancer. Intestinal metaplasia has been the focus of great fascination by many pathologists, because it was unexpected to find intestinal type mucosa containing goblet cells in the body or antrum of the stomach. Numerous studies have implicated intestinal metaplasia as a useful biomarker for gastric cancer risk, and even possibly a precursor to gastric malignancy. However, this evidence has been largely correlative. In patients with gastric cancer, intestinal metaplasia is frequently found in the stomach, even with early gastric cancer. Intestinal metaplasia is much more prevalent in high-risk areas for gastric cancer compared with low-risk areas. Finally, in several studies where serial endoscopies and biopsies were performed, patients with intestinal metaplasia, particularly type III, frequently developed gastric cancer.² Rokkas T. Filipe M.I. Sladen G.E. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut. 1991; 32 : 1110-1113 Crossref PubMed Scopus (196) Google Scholar Intestinal metaplasia has been used as the key biomarker in studies of Helicobacter pylori eradication or gastric cancer prevention, defining the preneoplastic lesion often considered the “point of no return.”³ Zivny J. Wang T.C. Yantiss R. et al. 2003 Role of therapy or monitoring in preventing progression to gastric cancer. J Clin Gastroenterol. 2003; 36 : S50-S60 Crossref PubMed Scopus (20) Google Scholar Indeed, because the gastric cancers that developed in this setting also showed intestinal differentiation, it seemed logical to conclude that the cancers arose directly from these intestinal metaplastic cells. Nevertheless, in contrast with other neoplasms, little genetic mutational evidence exists to implicate intestinal metaplastic lineages as true direct precursors of gastric neoplasia.

The Rab GTPases are the largest family of proteins regulating membrane traffic. Rab proteins form a nidus for the assembly of multiprotein complexes on distinct vesicle membranes to regulate particular membrane trafficking pathways. Recent investigations have demonstrated that Myosin Vb (Myo5B) is an effector for Rab8a, Rab10, and Rab11a, all of which are implicated in regulating different pathways for recycling of proteins to the plasma membrane. It remains unclear how specific interactions of Myo5B with individual Rab proteins can lead to specificity in the regulation of alternate trafficking pathways. We examined the relative contributions of Rab/Myo5B interactions with specific pathways using Myo5B mutants lacking binding to either Rab11a or Rab8a. Myo5B Q1300L and Y1307C mutations abolished Rab8a association, whereas Myo5B Y1714E and Q1748R mutations uncoupled association with Rab11a. Expression of Myo5B tails containing these mutants demonstrated that Rab11a, but not Rab8a, was required for recycling of transferrin in nonpolarized cells. In contrast, in polarized epithelial cyst cultures, Myo5B was required for apical membrane trafficking and de novo lumen formation, dependent on association with both Rab8a and Rab11a. These data demonstrate that different combinations of Rab GTPase association with Myo5B control distinct membrane trafficking pathways.