Kadir Akdemir
@kcakdemir.bsky.social
Husband & father | Asst prof at MD Anderson Cancer Center | Our lab focuses on tumor evolution, chromatin folding & instability
akdemirlab.github.io
akdemirlab.github.io
We compared ecDNA structure and transcription in two tumors: in P59, EGFR and CDK4 were predicted to be on separate ecDNAs; in P68, on the same ecDNA. Xenium data showed stronger EGFR-CDK4 expression correlation in P68 compared to p59.
May 22, 2025 at 5:37 PM
We compared ecDNA structure and transcription in two tumors: in P59, EGFR and CDK4 were predicted to be on separate ecDNAs; in P68, on the same ecDNA. Xenium data showed stronger EGFR-CDK4 expression correlation in P68 compared to p59.
We found that ecDNA+ tumors form nuclear EGFR transcriptional hubs.
EGFR FISH on post-Xenium slides showed >70% of these hubs localized to the nucleus and overlapped with EGFR copy number - unlike control gene FABP7 with similar expression but no hub formation.
EGFR FISH on post-Xenium slides showed >70% of these hubs localized to the nucleus and overlapped with EGFR copy number - unlike control gene FABP7 with similar expression but no hub formation.
May 22, 2025 at 5:37 PM
We found that ecDNA+ tumors form nuclear EGFR transcriptional hubs.
EGFR FISH on post-Xenium slides showed >70% of these hubs localized to the nucleus and overlapped with EGFR copy number - unlike control gene FABP7 with similar expression but no hub formation.
EGFR FISH on post-Xenium slides showed >70% of these hubs localized to the nucleus and overlapped with EGFR copy number - unlike control gene FABP7 with similar expression but no hub formation.
We found that EGFR ecDNA tumors are hypoxic, mesenchymal-rich, and pericyte-enriched.
May 22, 2025 at 5:37 PM
We found that EGFR ecDNA tumors are hypoxic, mesenchymal-rich, and pericyte-enriched.
Given our comprehensive whole-genome sequnecing datasets, we compared the spatial organization of ecDNA vs Linear Amplification GBMs
May 22, 2025 at 5:37 PM
Given our comprehensive whole-genome sequnecing datasets, we compared the spatial organization of ecDNA vs Linear Amplification GBMs
We found that IDH-mutant gliomas frequently harbored inflammatory microglia expressing CX3CR1 specifically within AC-like malignant neighborhoods, rather than OPC-like niches—despite the OPC-like malignant cell state being more prevalent in IDH-mutant gliomas.
May 22, 2025 at 5:37 PM
We found that IDH-mutant gliomas frequently harbored inflammatory microglia expressing CX3CR1 specifically within AC-like malignant neighborhoods, rather than OPC-like niches—despite the OPC-like malignant cell state being more prevalent in IDH-mutant gliomas.
To investigate the spatial tumor microenvironment of our glioma samples, we applied a single-cell spatial transcriptomics approach (10x Xenium), generating 4.6 million cells and over 775 million transcripts.
We identified distinct cell states in IDH-wildtype vs mutant gliomas
We identified distinct cell states in IDH-wildtype vs mutant gliomas
May 22, 2025 at 5:37 PM
To investigate the spatial tumor microenvironment of our glioma samples, we applied a single-cell spatial transcriptomics approach (10x Xenium), generating 4.6 million cells and over 775 million transcripts.
We identified distinct cell states in IDH-wildtype vs mutant gliomas
We identified distinct cell states in IDH-wildtype vs mutant gliomas
We next asked whether treatment contributed to ecDNA loss in recurrences. Recurrent tumors arose from residual regions of the primary site, suggesting ecDNAs were spatially restricted subclones eliminated during initial surgery.
May 22, 2025 at 5:37 PM
We next asked whether treatment contributed to ecDNA loss in recurrences. Recurrent tumors arose from residual regions of the primary site, suggesting ecDNAs were spatially restricted subclones eliminated during initial surgery.
We also examined EGFR expression levels, which showed a marked reduction in the recurrent tumors. Similarly, single-nucleus whole-genome analysis revealed the disappearance of the focal amplification on chromosome 7, while clonal alterations were retained.
May 22, 2025 at 5:37 PM
We also examined EGFR expression levels, which showed a marked reduction in the recurrent tumors. Similarly, single-nucleus whole-genome analysis revealed the disappearance of the focal amplification on chromosome 7, while clonal alterations were retained.
Hi-C and WGS data revealed the loss of ecDNA signals in recurrent tumor (P-12r1) while preserving other structural variations, such as chromothripsis on chr 3
May 22, 2025 at 5:37 PM
Hi-C and WGS data revealed the loss of ecDNA signals in recurrent tumor (P-12r1) while preserving other structural variations, such as chromothripsis on chr 3
We also identified two GBM patients (P12 and P29) in whom ecDNA molecules were not implicated in tumor recurrence and were absent in both subsequent surgical specimens.
May 22, 2025 at 5:37 PM
We also identified two GBM patients (P12 and P29) in whom ecDNA molecules were not implicated in tumor recurrence and were absent in both subsequent surgical specimens.
Hi-C and long-read data were essential to improve ecDNA reconstructions.
For example, for p59, the short-read reconstruction suggested EGFR and CDK4 genes are on the same ecDNA circle.
However, Hi-C and ONT WGS-based reconstructions suggested these genes reside on two distinct circles.
For example, for p59, the short-read reconstruction suggested EGFR and CDK4 genes are on the same ecDNA circle.
However, Hi-C and ONT WGS-based reconstructions suggested these genes reside on two distinct circles.
May 22, 2025 at 5:37 PM
Hi-C and long-read data were essential to improve ecDNA reconstructions.
For example, for p59, the short-read reconstruction suggested EGFR and CDK4 genes are on the same ecDNA circle.
However, Hi-C and ONT WGS-based reconstructions suggested these genes reside on two distinct circles.
For example, for p59, the short-read reconstruction suggested EGFR and CDK4 genes are on the same ecDNA circle.
However, Hi-C and ONT WGS-based reconstructions suggested these genes reside on two distinct circles.
🔹 Resolving ecDNA Structure and Function
We used short- and long-read whole-genome sequencing plus Hi-C to reconstruct complex extrachromosomal DNA (ecDNA) structures. This revealed:
Tumors can harbor multiple ecDNA circles with distinct oncogenes.
We used short- and long-read whole-genome sequencing plus Hi-C to reconstruct complex extrachromosomal DNA (ecDNA) structures. This revealed:
Tumors can harbor multiple ecDNA circles with distinct oncogenes.
May 22, 2025 at 5:37 PM
🔹 Resolving ecDNA Structure and Function
We used short- and long-read whole-genome sequencing plus Hi-C to reconstruct complex extrachromosomal DNA (ecDNA) structures. This revealed:
Tumors can harbor multiple ecDNA circles with distinct oncogenes.
We used short- and long-read whole-genome sequencing plus Hi-C to reconstruct complex extrachromosomal DNA (ecDNA) structures. This revealed:
Tumors can harbor multiple ecDNA circles with distinct oncogenes.
Excited to share our latest manuscript www.biorxiv.org/content/10.1...
This was a great collaboration with Drs. Huse, Lang, @jesserdixon.bsky.social
This was a great collaboration with Drs. Huse, Lang, @jesserdixon.bsky.social
May 22, 2025 at 5:37 PM
Excited to share our latest manuscript www.biorxiv.org/content/10.1...
This was a great collaboration with Drs. Huse, Lang, @jesserdixon.bsky.social
This was a great collaboration with Drs. Huse, Lang, @jesserdixon.bsky.social
One of the most aggressive tumors in our cohort—where the patient sadly survived only 1 month after brain metastasis diagnosis—harbored **3** distinct extra-chromosomal amplification molecules. Single-cell WGS showed these amplifications exist in the same cells. #CancerGenomics
February 28, 2025 at 2:27 PM
One of the most aggressive tumors in our cohort—where the patient sadly survived only 1 month after brain metastasis diagnosis—harbored **3** distinct extra-chromosomal amplification molecules. Single-cell WGS showed these amplifications exist in the same cells. #CancerGenomics
While analyzing our Xenium data, we discovered that DAPI images, routinely taken for cell segmentation, can also be used to identify micronuclei in tumor sections. Super excited about this—now we can study micronuclei in the tumor microenvironment!
February 28, 2025 at 2:27 PM
While analyzing our Xenium data, we discovered that DAPI images, routinely taken for cell segmentation, can also be used to identify micronuclei in tumor sections. Super excited about this—now we can study micronuclei in the tumor microenvironment!
An outlier in our study! The only non-ERBB2 amplified tumor had high T-cell infiltration in the brain metastasis. Notably, this patient received immune checkpoint blockade and responded exceptionally well—surviving 35+ months!
February 28, 2025 at 2:27 PM
An outlier in our study! The only non-ERBB2 amplified tumor had high T-cell infiltration in the brain metastasis. Notably, this patient received immune checkpoint blockade and responded exceptionally well—surviving 35+ months!
We used Xenium single-cell spatial transcriptomics to analyze the tumor microenvironment in primary and matched brain metastases. Findings? High immune cell infiltration in primary tumors, but a stark immune desert in brain metastases (which makes sense given previous brain spatial studies).
February 28, 2025 at 2:27 PM
We used Xenium single-cell spatial transcriptomics to analyze the tumor microenvironment in primary and matched brain metastases. Findings? High immune cell infiltration in primary tumors, but a stark immune desert in brain metastases (which makes sense given previous brain spatial studies).
The only patient in our EAC brain metastasis cohort treated with Enhertu had a remarkable response. Despite leptomeningeal disease—typically associated with a poor prognosis—this patient has survived 34+ months since diagnosis and is even off therapy due to continued success.
February 28, 2025 at 2:27 PM
The only patient in our EAC brain metastasis cohort treated with Enhertu had a remarkable response. Despite leptomeningeal disease—typically associated with a poor prognosis—this patient has survived 34+ months since diagnosis and is even off therapy due to continued success.
Analysis of multi-region whole-genome sequencing data from two patients revealed that ERBB2 amplifications arise early in tumor evolution, with consistently high ERBB2 copy number (CN) levels detected across all tumor samples.
February 28, 2025 at 2:27 PM
Analysis of multi-region whole-genome sequencing data from two patients revealed that ERBB2 amplifications arise early in tumor evolution, with consistently high ERBB2 copy number (CN) levels detected across all tumor samples.
Nora first analyzed whole-genome sequencing data from our brain metastasis cohort. She compared her findings with primary EAC (n=85) and the Hartwig EAC metastases to non-brain sites (n=140)
90% of EAC brain metastases harbor ERBB2 amplifications —MUCH higher than primary EAC (~20%).
90% of EAC brain metastases harbor ERBB2 amplifications —MUCH higher than primary EAC (~20%).
February 28, 2025 at 2:27 PM
Nora first analyzed whole-genome sequencing data from our brain metastasis cohort. She compared her findings with primary EAC (n=85) and the Hartwig EAC metastases to non-brain sites (n=140)
90% of EAC brain metastases harbor ERBB2 amplifications —MUCH higher than primary EAC (~20%).
90% of EAC brain metastases harbor ERBB2 amplifications —MUCH higher than primary EAC (~20%).
Really excited to share our lab's first manuscript! I cant be more proud of our team, especially @nora-mae.bsky.social who diligently worked on this project.
It will be a long thread but I promise it's worth it!
#Oncology #BrainMets
It will be a long thread but I promise it's worth it!
#Oncology #BrainMets
February 28, 2025 at 2:27 PM
Really excited to share our lab's first manuscript! I cant be more proud of our team, especially @nora-mae.bsky.social who diligently worked on this project.
It will be a long thread but I promise it's worth it!
#Oncology #BrainMets
It will be a long thread but I promise it's worth it!
#Oncology #BrainMets
Hopefully 2025 will be as fun/interesting as it’s mathematically. Happy New Year!!! (Credit: Moshe Verdi - I couldn’t find him here)
January 1, 2025 at 11:12 PM
Hopefully 2025 will be as fun/interesting as it’s mathematically. Happy New Year!!! (Credit: Moshe Verdi - I couldn’t find him here)