Inducible loss of one <i>Apc</i> allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis

Powell, Anne; Vlacich, Gregory; Zhao, Zhen-Yang; McKinley, Eliot T.; Washington, Mary Kay; Manning, H. Charles; Coffey, Robert J.

doi:10.1152/ajpgi.00358.2013

Cited by 56 publications

(68 citation statements)

References 27 publications

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“…Recently, Powell and colleagues (Powell et al ., 2014) have reported the development of a superior mouse model of familial adenomatous polyposis (FAP). FAP arises from germline mutations in the APC (adenomatous polyposis coli) tumor suppressor with multiple colonic tumors arising early in life, subsequent to loss of the remaining APC allele.…”

Section: Knowledge Gained From Lrig Mouse Modelsmentioning

confidence: 99%

The LRIG family: enigmatic regulators of growth factor receptor signaling

Simion¹,

Cedano-Prieto²,

Sweeney³

2014

Endocrine-Related Cancer

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The LRIG (leucine-rich repeats and immunoglobulin-like domains) family of transmembrane proteins contains three vertebrate members (LRIG1, LRIG2, LRIG3) and one member each in flies (Lambik) and worms (Sma-10). LRIGs have stepped into the spotlight as essential regulators of growth factor receptors, including receptor tyrosine and serine/threonine kinases. LRIGs have been found to both negatively (LRIG1, LRIG3) and positively (Sma-10, LRIG3) regulate growth factor receptor expression and signaling, although the precise molecular mechanisms by which LRIGs function are not yet understood. The most is known about LRIG1, which was recently demonstrated to be a tumor suppressor. Indeed, in vivo experiments reinforce the essential link between LRIG1 and repression of its targets for tissue homeostasis. LRIG1 has also been identified as a stem cell marker and regulator of stem cell quiescence in a variety of tissues, discussed within. Comparably less is known about LRIG2 and LRIG3 although studies to date suggest that their functions are largely distinct from LRIG1 and that they likely do not serve as growth/tumor suppressors. Finally, the translational applications of expressing soluble forms of LRIG1 in LRIG1-deficient tumors are being explored and hold tremendous promise.

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Section: Knowledge Gained From Lrig Mouse Modelsmentioning

confidence: 99%

The LRIG family: enigmatic regulators of growth factor receptor signaling

Simion¹,

Cedano-Prieto²,

Sweeney³

2014

Endocrine-Related Cancer

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“…Based on the adenoma-to-carcinoma model of linear evolution it has been assumed that the pool of normal colorectal stem cells in the crypts is likely the initial target of genomic events that initiates intestinal carcinogenesis, thus becoming founder clones (4–6). Moreover, the process of crypt fission, which is infrequently observed in normal colorectal mucosa (7), is definitely increased in colorectal adenomas (8), thus providing a plausible explanation for the geographical expansion of mutant clones harboring genomic events (9, 10).…”

Section: Introductionmentioning

confidence: 99%

“…Progression along the normal mucosa-adenoma-carcinoma sequence in colorectal cancer (CRC) is fostered by progressive accumulation of genomic events in well-known driver genes with the truncal events being the acquisition of APC alterations in approximately 85% of cases (12). APC hits targeting the stem cells of the colorectal crypt will induce proliferation of founder clones carrying these alterations in all dysplastic, and later cancerous cells, across all stages of carcinogenesis (truncal and driver events) (5, 6). …”

Section: Introductionmentioning

confidence: 99%

Mutational Heterogeneity in APC and KRAS Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis

Gausachs

Borràs

Chang

et al. 2017

Clinical Cancer Research

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Purpose The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer (CRC) are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model. Experimental design High-depth next-generation sequencing and SNP arrays were performed in whole lesion extracts of 37 FAP colorectal adenomas. Also, ultra-sensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies (n=59) and crypts (n=591) from 18 adenomas and 7 carcinomas and adjacent normal tissues. Results Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultra-sensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas, whereas abundant wild-type APC crypts were detected in adenomas. KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Non-random heterogeneity among crypts was also observed. Conclusions The striking degree of non-random intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis.

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“…Indeed, increased Wnt/β-catenin signaling in Lgr5+, Bmi1+, or Lrig1+ ISCs, as well as Ah -cre cells in the transit amplifying (TA) compartment, have been shown to rapidly promote tumorigenesis (Barker, et al 2009; Powell, et al 2014; Sangiorgi and Capecchi 2008). The phosphoinositide-3-kinase (PI3K)-Akt pathway, which is commonly deregulated in human colorectal cancer, has been causally linked to tumor development in rodents, independent of canonical Wnt signaling, via PIK3CA mutations (Leystra, et al 2012) or Pten inactivation in the intestinal epithelium (Byun, et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis

Tabrizian

Wang

Guan

et al. 2017

Endocrine-Related Cancer

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Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis following inactivation of Apc. However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 mo and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP Ptenflox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14–15 mo of age. Finally, various combinations of Lgr5+-ISC specific, Apc and Pten-deleted mice were generated, and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU positive cells in the small intestine (P<0.05). However, combining Pten and Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion (P<0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that Pten deficiency, is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining Pten and Apc deficiency in ISCs synergistically increases proliferation, tumor formation, and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ISC-derived tumorigenesis.

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Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis

Cited by 56 publications

References 27 publications

The LRIG family: enigmatic regulators of growth factor receptor signaling

The LRIG family: enigmatic regulators of growth factor receptor signaling

Mutational Heterogeneity in APC and KRAS Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis

Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis

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